The toxin producing bacterium Clostridium difficile causes an estimated 1,000,000 to 3,000,000 cases of diarrhea and colitis in the United States each year at an annual cost of $1.1 Billion dollars for nosocomial infections alone. Most cases are associated with the administration of broad-spectrum antibiotics. It has been assumed that the administration of antibiotics causes changes in the normal gastrointestinal microbiota. These changes allow overgrowth of C. difficile, which has either been present in low numbers in the gastrointestinal tract before the administration of antibiotics, or is acquired from the environment during antibiotic administration. Furthermore, it is likely that C. difficile spores and not the vegetative bacilli are the direct contagion analogous to other pathogenic Clostridia sp. Spores are hardy, not easily cleared from the body by natural means and are resistant to antibiotics. We theorize that the normal gastrointestinal microbiota interferes with gut colonization by C. difficile and may also regulate expression of toxin by the organism. Additionally, we hypothesize that the spore morphotype itself contributes heavily to not only the initial introduction of C. difficile to the host, but also to recurrent relapse and shedding/transmission. To address these hypotheses, three specific aims are proposed for this project. In the first aim, we will compare the fecal microbiota in asymptomatically colonized individuals and patients with initial or recurrent C. difficile infection of varied severity. We will determine if specific community structures correlate with susceptibility to disease and with clinical outcomes/severity.
The second aim will extend these observations in a murine model of C. difficile infection to define the microbiologic factors that contribute to colonization resistance against C. difficile. In the third aim the contribution of germination and sporulation to clinical disease and transmission will be determined. We will characterize clinical C. difficile isolates for sporulation/germination attributes and test naturally occurring variants and defined mutants in the murine C. difficile model.
These aims will provide important insight in the roles of microbial ecology and molecular bacterial pathogenesis in C. difficile infection.

Public Health Relevance

Treatment with antibiotics can lead to infection and disease with the bacterium Clostridium difficile. The proposed research will study the role ofthe existing gut bacteria and the ability ofthe pathogen to form spores in disease related to C. difficile infection. The overall goal is to increase our ability to come up with novel ways to prevent and treat this important human infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI090871-05
Application #
8701177
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Theriot, Casey M; Bowman, Alison A; Young, Vincent B (2016) Antibiotic-Induced Alterations of the Gut Microbiota Alter Secondary Bile Acid Production and Allow for Clostridium difficile Spore Germination and Outgrowth in the Large Intestine. mSphere 1:
Seekatz, Anna Maria; Rao, Anna Maria; Santhosh, Kavitha et al. (2016) Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med 8:47
Leslie, Jhansi L; Young, Vincent B (2016) A whole new ball game: Stem cell-derived epithelia in the study of host-microbe interactions. Anaerobe 37:25-8
Rao, Krishna; Santhosh, Kavitha; Mogle, Jill A et al. (2016) Elevated fecal calprotectin associates with adverse outcomes from Clostridium difficile infection in older adults. Infect Dis (Lond) 48:663-9
Young, V B (2016) Therapeutic manipulation of the microbiota: past, present, and considerations for the future. Clin Microbiol Infect 22:905-909
Stokely, Janelle N; Niendorf, Sandra; Taube, Stefan et al. (2016) Prevalence of human norovirus and Clostridium difficile coinfections in adult hospitalized patients. Clin Epidemiol 8:253-60
McDermott, Andrew J; Falkowski, Nicole R; McDonald, Roderick A et al. (2016) Interleukin-23 (IL-23), independent of IL-17 and IL-22, drives neutrophil recruitment and innate inflammation during Clostridium difficile colitis in mice. Immunology 147:114-24
Rogers, M A M; Aronoff, D M (2016) The influence of non-steroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect 22:178.e1-9
Young, Vincent B; Hayden, Mary K (2016) Environmental management in the gut: fecal transplantation to restore the intestinal ecosystem. Infect Dis (Lond) 48:593-5
Micic, Dejan; Rao, Krishna; Trindade, Bruno Caetano et al. (2015) Serum 25-Hydroxyvitamin D Levels are not Associated with Adverse Outcomes in Clostridium Difficile Infection. Infect Dis Rep 7:5979

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